[Show abstract][Hide abstract] ABSTRACT: Advanced glycation end products (AGEs) and their receptor (RAGE) have a role in diabetic nephropathy. We have recently found that linagliptin, an inhibitor of dipeptidyl peptidase-4 (DPP-4), could inhibit renal damage in type 1 diabetic rats by suppressing the AGE-RAGE axis. However, it remains unclear whether DPP-4 deficiency could also have beneficial effects on experimental diabetic nephropathy. To address the issue, we rendered wild-type F344/NSlc and DPP-4-deficient F344/DuCrl/Crlj rats diabetic by injection of streptozotocin, and then investigated whether DPP-4 deficiency could block the activation of AGE-RAGE axis in the diabetic kidneys and resultantly ameliorate renal injury in streptozotocin-induced diabetic rats. Compared with control rats at 9 and 11 weeks old, body weight and heart rates were significantly lower, while fasting blood glucose was higher in wild-type and DPP-4-deficient diabetic rats at the same age. There was no significant difference of body weight, fasting blood glucose and lipid parameters between the two diabetic rat strains. AGEs, 8-hydroxy-2'-deoxyguanosine (8-OHdG) and nitrotyrosine levels in the kidney, renal gene expression of RAGE and intercellular adhesion molecule-1, glomerular area, urinary excretion of 8-OHdG and albumin, and the ratio of renal to body weight were increased in wild-type diabetic rats at 9 and/or 11 weeks old compared with age-matched control rats, all of which except for urinary 8-OHdG levels at 11 weeks old were significantly suppressed in DPP-4-deficient diabetic rats. Our present study suggests that DPP-4 deficiency could exert beneficial actions on type 1 diabetic nephropathy partly by blocking the AGE-RAGE axis. DPP-4 might be a novel therapeutic target for preventing diabetic nephropathy.Laboratory Investigation advance online publication, 2 March 2015; doi:10.1038/labinvest.2015.35.
No preview · Article · Mar 2015 · Laboratory Investigation
[Show abstract][Hide abstract] ABSTRACT: Food or supplement-derived L-carnitine is changed to trimethylamine (TMA) by interstinal microbiota, which is further metabolized to trimethylamine-N-oxide (TMAO), being involved in the promotion of atherosclerosis in animal models. Meanwhile, carnitine deficiency has played a role in accelerated atherosclerosis in hemodialysis (HD) patients. However, effects of oral L-carnitine supplementation on circulating levels of TMAO and markers of vascular injury and oxidative stress in patients on HD remain unclear. In this study, we addressed the issue.
Thirty-one HD patients with carnitine deficiency were treated with oral L-carnitine (900mg/day) for 6 months. At baseline and after treatment, clinical variables including circulating levels of carnitine fractions, TMA, TMAO, advanced glycation end products (AGE), soluble forms of intracellular adhesion molecule-1 (sICAM-1), vascular cell adhesion molecule-1 (sVCAM-1), and malondialdehyde (MDA) were measured.
Oral L-carnitine supplementation significantly increased total, free, and acyl carnitine, and plasma TMA and TMAO levels, whereas it decreased markers of vascular injury and oxidative stress such as sICAM-1, sVCAM-1, and MDA levels. TMA and TMAO levels at baseline were correlated with each other, and free carnitine was independently associated with TMAO levels. Further, change in AGE values from baseline ([INCREMENT]AGE) was positively correlated with [INCREMENT]sICAM-1 (p=0.043), and was a sole independent determinant of [INCREMENT]sICAM-1 (R2=0.133, p=0.043).
The present study demonstrated that although oral L-carnitine supplementation was associated with increased TMAO levels, it might be beneficial on vascular injury in patients on HD. Vasculoprotective properties of L-carnitine supplementation in HD patients might be ascribed partly to its inhibitory actions on AGE.
No preview · Article · Jan 2015 · Journal of Cardiovascular Pharmacology
[Show abstract][Hide abstract] ABSTRACT: Corresponding author at: Department of Pathophysiology and Therapeutics of Diabetic Vascular Complications, Kurume University School of Medicine, 67 Asahi-machi, Kurume 830-0011, Japan.
No preview · Article · Jan 2015 · Thrombosis Research
[Show abstract][Hide abstract] ABSTRACT: Receptor for advanced glycation endproducts (RAGE) is a multiligand receptor of the immunoglobulin superfamily, which binds not only to advanced glycation endproducts, but also to high-mobility group box-1, S100/calgranulins, amyloid fibrils, and lipopolysaccharide. We discuss the pathophysiological role of RAGE in both diabetic and nondiabetic progressive renal diseases, and its potential use for therapeutic interventions in these devastating disorders.
Although initial studies about RAGE focused on diabetic nephropathy, a number of recent findings have revealed that RAGE also actively participates in the pathogenesis of nondiabetic progressive renal diseases, including hypertensive nephropathy, obesity-related glomerulopathy, lupus nephritis, autosomal dominant polycystic kidney disease, renal amyloidosis, and septic acute kidney injury. Furthermore, blocking the RAGE by a neutralizing antibody or genetic deletion of RAGE was found to prevent the development and progression of various renal disorders.
The interaction of several RAGE ligands with RAGE plays a role in a broad range of progressive kidney diseases. The blockade of the various RAGE ligands-RAGE interactions might be a novel therapeutic strategy for preventing the development and progression of numerous progressive kidney diseases.
No preview · Article · Jan 2015 · Current Opinion in Nephrology and Hypertension
[Show abstract][Hide abstract] ABSTRACT: Advanced glycation endproducts (AGEs) and their receptor (RAGE) play a role in vascular complications in diabetes. We have previously shown that 17β-estradiol at 10 nmol/l, a nearly identical plasma concentration to that during mid-pregnancy, up-regulates RAGE expression in endothelial cells. The finding might suggest the involvement of 17β-estradiol in the deterioration of vascular complications in diabetes during pregnancy. However, the effects of the selective estrogen receptor modulator, bazedoxifene, on oxidative and inflammatory reactions in AGEs-exposed endothelial cells remain unknown. In this study, we addressed the issue. Ten nmol/l 17β-estradiol increased RAGE and monocyte chemoattractant protein-1 (MCP-1) gene and protein expression in human umbilical vein endothelial cells (HUVECs), both of which were blocked by 10 nmol/l bazedoxifene. Bazedoxifene at 10 nmol/l also significantly inhibited the AGEs-induced superoxide generation, RAGE and MCP-1 gene and protein expression in HUVECs. The present study suggests that blockade of the AGEs–RAGE axis by bazedoxifene might be a novel therapeutic target for preventing vascular damage in diabetes, especially in postmenopausal women.
[Show abstract][Hide abstract] ABSTRACT: Carnitine deficiency may contribute to cardiovascular disease (CVD) in patients with hemodialysis (HD). Dyslipidemia plays a role in CVD and its prevalence is also high in HD patients. We examined here the effects of switching from oral administration (PO) to intravenous (IV) injection of l-carnitine on lipid metabolism in patients with HD.
Nine HD patients who had received l-carnitine orally (900 mg/day) for 1 year were enrolled in this study. We examined whether lipid parameters were improved by switching to IV injection therapy of 1000 mg l-carnitine.
IV injection of l-carnitine for 1 week significantly increased total, free and acyl carnitine levels both before and after HD. Switching to IV injection therapy for 1 and 4 weeks decreased serum free fatty acid (FFA) (322 ± 104 versus 261 ± 124 µmol/L) and increased high-density lipoprotein-cholesterol levels (1.46 ± 0.49 versus 1.63 ± 0.62 mmol/L), respectively. Change in FFA values from the baseline (ΔFFA) was positively correlated with the Δacyl/free carnitine ratio (r (2) = 0.553, P = 0.022).
This study demonstrated that switching to IV l-carnitine therapy from oral supplementation improved lipid profiles, thus supporting the clinical utility of IV administration of l-carnitine for the treatment of patients on HD.